The goal of this research is to determine whether the peptide neurotransmitter hypocretin (orexin) mediates reward or dysphoria, and if hypocretin's cotransmitter dynorphin modulates or enhances either of these effects. These questions will be addressed with a combination of molecular genetic techniques and classic behaviors of hedonic state. Recent reports suggest that hypocretin mediates the rewarding effect;of drugs of abuse. In contrast, it has also been proposed that hypocretin determines the aversive effects of stress that are known to precipitate relapses in drug taking. Chronic stress and drug use also cause enduring increases in expression of dynorphin which may mediate the dysphoria associated with stress and drug withdrawal. The expression of both peptides by neurons that send projections to critical odes of the mesolimbic dopamine system (nucleus accumbens, ventral tegmental area/VTA) suggests that;they may interact to influence the activity of this system and determine its responsiveness to drugs of abuse. In Aim 1, the rewarding effects of cocaine in mice with germline deletion of the gene encoding hypocretin will be assessed using intracranial self-stimulation (ICSS). Mean ICSS threshold measures taken after different doses of cocaine will be used to determine whether genetically ablated hypocretin function attenuates or enhances cocaine's rewarding effects. In Aim 2, the dysphoric effects of the kappa opioid receptor (KOR) agonist U50.588 will be evaluated in the same line of hypocretin knockout mice using ICSS. As above, dose-response effects on ICSS threshold will be used to determine whether the loss of hypocretin signalling enhances or attenuates the dysphoric effects of KOR activation. In Aim 3, the effects of exogenous hypocretin on place conditioning will be examined in wildtype controls or transgenic mice in which KOR has been deleted from VTA dopamine neurons by viral gene transfer. Whether place preference or aversion established by hypocretin can be affected by deletion of KOR in VTA is the principle outcome measure. Clarifying the hypocretin system's hedonic properties and the manner in which they are influenced by dynorphin transmission provides basic information about the brain's mechanisms for processing affect, additionally, this work will study the hypocretin-dynorphin system as a novel therapeutic target for the treatment of drug addiction.